Variant classified as Uncertain Significance - Favor Benign. The Thr124Ile varia nt in LAMP2 has not been previously reported, but has previously been identified in one individual with HCM by our laboratory. This variant has not been identif ied in large and broad populations by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS). This low frequency supports a pathogenic role. Howe ver, threonine (Thr) at position 124 is not conserved in mammals or chicken, red ucing the likelihood that the change is pathogenic. In addition, pathogenic miss ense variants are rare in the LAMP2 gene, as most disease causing variants lead to a loss of function. Computational analyses (biochemical amino acid properties , AlignGVGD, PolyPhen2, and SIFT) suggest that the Thr124Ile variant may not imp act the protein, though this information is not predictive enough to rule out pa thogenicity. In summary, although this data suggests that the Thr124Ile variant is likely benign, in the absence of additional information its clinical signific ance cannot be determined.

The c.371C>T (p.T124I) alteration is located in exon 3 (coding exon 3) of the LAMP2 gene. This alteration results from a C to T substitution at nucleotide position 371, causing the threonine (T) at amino acid position 124 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 124 of the LAMP2 protein (p.Thr124Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 32150461). ClinVar contains an entry for this variant (Variation ID: 44428). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LAMP2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.